Troglitazone to remain on shelves for now
FDA panel votes against further monotherapy use
The controversial antidiabetic troglitazone (Warner-Lambert) can remain on the market, but it should not be used as a monotherapy for the reduction of insulin resistance, the Food and Drug Administration’s Endocrinologic and Metabolic Drug Advisory Committee has recommended following a hearing earlier this year.
The panel voted 8-4 that the benefits of the drug outweigh its risks of causing acute liver failure if it is used with insulin or sulfonylureas.
The hearing was the result of mounting reports of adverse reactions associated with the drug, which to date include 43 reports of liver failure resulting in seven transplants and 28 patient deaths. The drug has had a checkered history since being approved by the FDA in 1997, the same year it was pulled off the market in the United Kingdom. (A 1998 petition to return the drug to the shelves there was denied.)
The drug debuted in the United States in January 1997, and by October a warning concerning liver failure and a recommendation for liver enzyme monitoring was added to the packaging. By December of that year, the warning was accentuated by a highlighted label on the packaging and the frequency of recommended monitoring increased. A "Dear Doctor" letter also was issued by the FDA in December, followed by a second in July 1998, as liver failure reports continued.
According to an agency summary of the advisory panel hearing, the FDA estimates that cases of liver failure are likely underreported by as much as one-tenth of the actual number, and physician compliance with baseline monitoring is "poor."
David Graham, MD, clinical regulatory specialist for the FDA’s Office of Postmarketing Risk Assessment, testified at the hearing that health officials are uncertain whether alanine transaminase (ALT) monitoring can ensure the prevention of fatalities based on data that level changes provided a clear warning in only 12 of the 43 documented cases. And, he said, of those 12 cases, ALT levels went from a normal reading to one of irreversibly acute liver failure in four to 34 days, which could elude the timeliness of monitoring protocols.
The current monitoring recommendations call for checking ALT levels at baseline for eight months, every other month for four months, then "periodically" thereafter. Use of the drug is not recommended if patients show evidence of "acute liver disease" or if ALT is greater than 1.5 times a patient’s upper-normal limit.
Liver function tests also are recommended if patients show symptoms of hepatic dysfunction. In addition, the FDA recommends weekly monitoring if ALT is between 1.5 and two times the upper limit of normal and complete stoppage of the drug if patients develop jaundice or ALT is greater than three times the upper-normal limit.
Warner Lambert’s proposal
At the hearing, Warner Lambert submitted a proposal to increase the potential safety of the drug again based on warnings, patient education, and the advent of a trial period of dosing.
In detail, Warner-Lambert offered to examine and identify specific patient groups that would benefit from the drug; recommend a trial dosing period that would continue only if patients respond according to specific time periods; beef up warnings by cautioning against using the drug in patients with a history of liver disease or alcohol abuse; and begin a physician and patient education program based on a monitoring reminder system.
The FDA is expected to consider the panel’s recommendation and determine the ultimate fate of the drug by the end of this year.
[For more information, contact the FDA Office of Postmarketing Risk Assessment at (301) 594-6822 or 594-5443 or Warner-Lambert at (973) 540-2000.]
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